Pathophysiology of Heart Failure with a Normal Ejection Fraction in the Elderly

描述(由申请人提供)：心力衰竭经常发生在射血分数(HFNEF)正常的患者中，受影响的对象主要是老年女性，有几种合并疾病。尽管这些患者存在不同的临床病理和合并症，但通常采用一种常见的病理生理学解释来解释他们的临床症状，向心性肥厚导致心腔体积较小，舒张期容量减少(特定充盈压力下的体积减少)。在这些患者中，需要较高的静息左心室充盈压才能维持正常的心输出量。我们的初步数据显示，尽管HFNEF通常被认为是单一血流动力学机制的结果，但亚型存在明显不同的潜在病理生理学。具体地说，我们记录了患有HFNEF的一个重要亚组的脑室容量增加和血浆容量扩大，这与容量超负荷状态一致。在正常射血分数的设置中，随着舒张末容量的增加，每搏出血量必须增加，表示高输出状态。高输出状态涉及外周(即心脏外)机制，包括贫血等。贫血可能是老年HFNEF患者运动不耐受、心室重构异常以及整体健康状况和生活质量受损的一个重要的、可改变的因素。我们的初步数据表明，在接受HFNEF治疗的老年患者中，贫血的患病率很高(&gt；50%)，这些受试者中的大多数(76%)通过血容量分析患有真正的贫血，这与肾小球滤过率有关，这表明促红细胞生成素的产生不足可能是他们贫血的一个机制。此外，我们还发现，与无贫血的老年HFNEF患者相比，贫血的HFNEF患者的生活质量更差，症状更严重，并伴有血流动力学和结构性心血管变化。最后，初步数据表明，对贫血的HFNEF受试者给予促红细胞生成素可以改善次极量和最大运动量。为了与我们阐明HFNEF综合征的病理生理机制和开发有效治疗方法的长期目标一致，我们建议评估HFNEF治疗老年患者贫血的影响。本研究的具体目的是对HFNEF纠正老年受试者贫血对腹核结构和功能、功能容量和整体健康状况的影响提供一个全面和机械的评估。我们建议在120名患有HFNEF的老年受试者中进行一项随机、前瞻性、双盲研究，以检验皮下注射促红细胞生成素将与显著逆转心室重构、增加运动能力和改善健康状况相关的假设。主要测量内容包括6分钟步行时间、最大耗氧量和呼气分析的无氧呼吸阈值；血容量分析、肾功能测量、标准化问卷测量；三维超声心动图测量左心室容量、质量和功能。这项研究将探讨贫血在老年HFNEF患者病理生理学中的作用，并确定靶向性贫血是否会影响心室重构和功能、运动能力和健康状况。贫血是导致HFNEF特征的容量超负荷状态的许多心外因素之一。。

DESCRIPTION (provided by applicant): Heart failure frequently occurs in patients with a normal ejection fraction (HFNEF) and affected subjects are predominately elderly, women with several co-morbid conditions. Despite the diversity of underlying clinical pathologies and co-morbid conditions present in these patients, a common pathophysiologic explanation is generally applied to explain their clinical symptoms, concentric hypertrophy leading to a small chamber size with decreased diastolic capacitance (decreased volume at a specific filling pressure). In such patients, the high resting left ventricular filling pressure is required for such hearts to maintain normal cardiac output. Our preliminary data revealed that although HFNEF is commonly thought of as being the result of a single hemodynamic mechanism, subgroups exist with distinctly different underlying pathophysiologies. Specifically, we documented that a significant subgroup with HFNEF have increases in ventricular volumes and expanded plasma volumes, consistent with a volume overload state. In the setting of a normal ejection fraction with end diastolic volume increased, stroke volume must increase, indicating a high output state. High output states involve peripheral (i.e.extra-cardiac) mechanisms, including anemia among others. Anemia may be an important, modifiable contributor to exercise intolerance in elderly HFNEF patients, abnormal ventricular remodeling and impaired overall health status and quality of life. Our pilot data suggests that the prevalence of anemia is high (> 50%) in elderly patients hospitalized with HFNEF, most of these subjects (76%) have a true anemia by blood volume analysis, which is associated with the glornerular filtration rate, suggesting that inadequate production of erythropoeitin may be a mechanism for their anemia. We have additionally, shown that anemic HFNEF subjects have poorer quality of life, more severe symptoms along with hemodynamic and structural cardiovascular changes compared with elderly subjects with HFNEF without anemia. Finally, preliminary data suggests that erythropoeitin adminstration to anemic HFNEF subjects results in improvements in submaximal and maximal exercise capacity. Concordant with our long-term goal to elucidate the pathophysiologic mechanisms that underlie the the syndrome of HFNEF and to develop effective therapies, we propose to evaluate the impact of treating anemia in elderly subjects with HFNEF. The specific aims of the current study are to provide a comprehensive and mechanistically based assessment of how correcting anemia in elderly subjects with HFNEF can impact on ventriuclar structure and funciton, functional capacity and overall health status. We propose to perform a randomized, prospective, double bind study in 120 elderly subjects with HFNEF to test the hypothesis that the administration of subcutaneous erythropoietin will be associated with significant reverse ventricular remodeling, increased exercise capacity and improved health status. Principle measurements will include six minute walk, maximal oxygen consumption and ventilatory anaerobic threshold by expired gas analysis; blood volume analysis, mesaures of renal function, health status by standardized questionnaires, and LV volumes, mass and function by three dimensional echocardiography. This study will examine the role of anemia in the pathophysiology of elderly patients with HFNEF and determine whether targeting anemia, one of many extra-cardiac factors that could contribute to the volume overload state that is characteristic of HFNEF, can ventricular remodeling and function, exercise capacity and health status. .